Folic Acid, Parental Mutation Rates and the Risk for Neural Tube Defects

叶酸、亲本突变率和神经管缺陷的风险

• 批准号: 8963563
• 负责人: RICHARD H. FINNELL
• 金额: $ 47.47万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963563
• 关键词: 8-hydroxy-2' -deoxyguanosine; Affect; Age; Antioxidants; Aromatic Polycyclic Hydrocarbons; Biological; Biological Models; Birth; Candidate Disease Gene; Cell Line; Childhood; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Congenital Abnormality; DNA Adducts; DNA Double Strand Break; DNA Sequence; Data; Databases; Developing Countries; Development; Diet; Embryo; Etiology; Exhibits; Fetus; Folic Acid; Food Supply; Frequencies; Gene Expression; Gene Proteins; Genes; Genetic Vectors; Healthcare; Heterozygote; Homozygote; Human; In Vitro; Individual; Infant; Intervention; Investigation; Knockout Mice; Knowledge; Medical; Mus; Mutagens; Mutation; Neural Tube Defects; Newborn Infant; Online Mendelian Inheritance In Man; Partner in relationship; Pathway interactions; Patients; Phase; Placenta; Point Mutation; Population Database; Pregnancy; Prevalence; Prevention; Prevention strategy; Property; Proteins; Reactive Oxygen Species; Research; Research Project Grants; Resistance; Risk; Sampling; Societies; Specific qualifier value; Spliced Genes; Structural Congenital Anomalies; Supplementation; Technology; Testing; Variant; base; cohort; effective intervention; fortification; genetic variant; genome sequencing; in vivo; male; member; mouse model; novel; novel strategies; offspring; oxidative DNA damage; planar cell polarity; prevent; programs; public health relevance; time interval

 DESCRIPTION (provided by applicant): Birth defects are among the leading pediatric healthcare issues, yet there are few prevention strategies and the prevalence of birth defects in the US has remained relatively stable for decades, despite folic acid fortification of the food supply. Neural tube defects (NTDs) are among the most common and serious of all birth defects affecting 0.5-1 per 1,000 US newborns, yet their complex etiology remains poorly understood (Wallingford et al., 2013). It is well established that pre-pregnancy supplementation with folic acid can reduce the risk of NTDs, but the underlying mechanism of this beneficial effect is unclear. Approximately 30% of NTDs cannot be prevented by maternal periconceptional folate supplementation. Our preliminary data showed that rare mutations in planar cell polarity (PCP) pathway could increase the risk of NTDs, while mutagens such as polycyclic aromatic hydrocarbons were enriched in the placentas of NTDs fetuses/infants. We hypothesized that NTDs are caused by combinations of rare multiple mutations. Higher mutation rates results in a higher NTDs prevalence. It is possible that folic acid can prevent NTDs by reducing the mutation rate. Furthermore, we hypothesize that paternal supplementation with folic acid can further reduce NTD rates. We have a unique opportunity to evaluate folate supplement effect on mutation rate by leveraging previously collected biological samples from NTD patients and controls from several distinct cohorts. Additionally, we propose to use mouse models to better understand the relationship between folate and mutation rates in vivo. The results of this study will provide an explanation of how folate prevents NTDs, and will reveal novel pathways for intervention on folate-resistant NTDs. Hence, the successful completion of the proposed studies is likely to have substantial impact on our understanding of conditions that affect ~6% of births worldwide and constitute one of the major healthcare concerns for the youngest members of society.

 描述(申请人提供)：出生缺陷是主要的儿科医疗保健问题之一，但几乎没有预防策略，尽管食品供应中添加了叶酸，但美国出生缺陷的流行率几十年来一直保持相对稳定。神经管缺陷(NTD)是所有出生缺陷中最常见和最严重的之一，影响每1000名美国新生儿中有0.5-1名，但其复杂的病因仍然知之甚少(Wallingford等人，2013年)。孕前补充叶酸可以降低NTDS的风险，这是公认的，但这种有益效果的潜在机制尚不清楚。大约30%的NTDS不能通过母体妊娠周补充叶酸来预防。我们的初步数据显示，平面细胞极性(PCP)途径的罕见突变会增加NTDS的风险，而NTDS胎儿/婴儿的胎盘中富含多环芳烃等诱变剂。我们假设NTDS是由罕见的多个突变组合引起的。更高的突变率会导致更高的NTDS患病率。叶酸可能通过降低突变率来预防NTDS。此外，我们假设父亲补充叶酸可以进一步降低NTD的发生率。我们有一个独特的机会，通过利用先前从NTD患者和来自几个不同队列的对照收集的生物样本来评估补充叶酸对突变率的影响。此外，我们建议使用小鼠模型来更好地了解体内叶酸和突变率之间的关系。这项研究的结果将为叶酸如何预防NTDS提供解释，并将揭示干预叶酸抵抗NTDS的新途径。因此，拟议研究的成功完成可能会对我们对影响全球约6%出生人口的疾病的理解产生重大影响，并构成社会最年轻成员的主要医疗保健问题之一。